Preliminary evaluation of patient radiation doses during radionuclide diagnostic with monoclonal antibodies labeled with ⁸⁹Zr

Abstract

In connection with the constantly increasing use of monoclonal antibodies labeled with ⁸⁹Zr, in clinical practice, it is urgent to study their pharmacokinetics with the determination, based on the data obtained, of absorbed doses in tumor foci, as well as intact organs and tissues, and effective doses of patients. To date, there are a limited number of studies that provide patient doses for diagnostic examinations using ⁸⁹Zr-labeled monoclonal antibodies. In this regard, the purpose of this work was to assess the biodistribution of various monoclonal antibodies (ramucirumab, trastuzumab, atezolizumab) labeled with ⁸⁹Zr, based on published data, with subsequent calculation of absorbed doses in radiosensitive organs and tissues and effective doses of patients.

Based on the analysis of experimental data on the biodistribution of monoclonal antibodies labeled with ⁸⁹Zr for the diagnosis of oncological diseases from the available literature sources and our own assessments, it has been concluded that the results of the determination of absorbed in organs and tissues and effective doses are inconsistent. The absorbed doses in organs, according to different literature sources, vary up to an order of magnitude within one organ and reach 440 mGy per examination, the effective dose varies from 3 to 112 mSv per examination. This may be due to differences in study design, radiometry and dose assessment methods. Comparison with doses obtained on the basis of a general model of biodistribution of monoclonal antibodies demonstrates the possibility of using this model for a rough estimate of internal doses of patients. However, for a more accurate assessment, it is necessary to standardize approaches to the determination of internal radiation doses using the most effective methodological solutions and software products.

Keywords

89Zr / monoclonal antibodies / radiopharmaceuticals / absorbed doses in organs / effective dose / ramucirumab / trastuzumab / atezolizumab

References

[1] Granov A. M., Tytin L. A., eds. Positron emission tomography: guideline for doctors. Saint Petersburg: Foliant; 2008. 368 p. (In Russ.).

[2] Гранов А. М. Позитронная эмиссионная томография: руководство для врачей / под редакцией А. М. Гранова и Л. А. Тютина. – Санкт-Петербург: Фолиант, 2008. – 368 с.

[3] Granov A. M., Tyutin L. A., Stanzhevskiy A. A., et al. Development and introduction into the clinical practice of new tumorotropic radiopharmaceuticals – a key aspect of the use of nuclear medicine in oncology. Luchevaya diagnostika i terapiya = Diagnostic radiology and radiotherapy. 2012;(4):11–21. (In Russ.).

[4] Гранов А. М. Разработка и внедрение в клиническую практику новых туморотропных радиофармпрепаратов – важнейший аспект использования достижений ядерной медицины в онкологической клинике / А. М. Гранов, Л. А. Тютин, А. А. Станжевский [и др.] // Лучевая диагностика и терапия. – 2012. – № 4. – С. 11–21.

[5] Granov A., Tyutin L., Schwarz Th., eds. Positron emission tomography. Heildelberg: Springer; 2013. 384 p.

[6] Positron emission tomography / eds. Granov A., Tyutin L., Schwarz Th. Heildelberg: Springer; 2013. 384 p.

[7] Vallabhajosula S. Molecular Imaging. Radiopharmaceuticals for PET and SPECT. Berlin; New York: Springer-Verlag; 2009. 371 p.

[8] Heskamp S., Raavé R., Boerman O., et al. 89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry. Bioconjug. Chem. 2017;28(9):2211–2223. https://doi.org/10.1021/acs.bioconjchem.7b00325.

[9] Heskamp S., Raavé R., Boerman O., et al. 89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry. Bioconjug. Chem. 2017;28(9):2211-2223. https://doi.org/10.1021/acs.bioconjchem.7b00325.

[10] Chernov V. I., Bragina O. D., Sinilkin I. G., et al. Radioimmunotherapy: Current state of the problem. Voprosy onkologii = Problems in oncology. 2016;62(1):24-30. (In Russ.)

[11] Чернов В. И. Радиоиммунотерапия: современное состояние проблемы / В. И. Чернов, О. Д. Брагина, И. Г. Синилкин [и др.] // Вопросы онкологии. – 2016. – Т. 62. – № 1. – С. 24–30.

[12] Kendi A. T., Moncayo V. M., Nye J. A., et al. Radionuclide Therapies in Molecular Imaging and Precision Medicine. PET Clin. 2017;12(1):93–103. https://doi.org/10.1016/j.cpet.2016.08.006.

[13] Kendi A. T., Moncayo V. M., Nye J. A., et al. Radionuclide Therapies in Molecular Imaging and Precision Medicine // PET Clin. 2017. Vol. 12, no. 1. P. 93–103. https://doi.org/10.1016/j.cpet.2016.08.006.

[14] Dijkers E. C., Kosterink J. G., Rademaker A. P., et al. Development and Characterization of Clinical-Grade 89Zr-Trastuzumab for HER2/neu ImmunoPET Imaging. J Nucl Med. 2009;50(6):974–981. https://doi.org/10.2967/jnumed.108.060392.

[15] Dijkers E. C., Kosterink J. G., Rademaker A. P., et al. Development and Characterization of Clinical-Grade 89Zr-Trastuzumab for HER2/neu ImmunoPET Imaging // J Nucl Med. 2009. Vol. 50, no. 6. P. 974–981. https://doi.org/10.2967/jnumed.108.060392.

[16] Verel I., Visser G. W. M., Boellaard R., et al. 89Zr immuno-PET: comprehensive procedures for the production of 89Zr labeled monoclonal antibodies. J Nucl Med. 2003;44(8):1271–1281.

[17] Verel I., Visser G. W. M., Boellaard R., et al. 89Zr immuno-PET: comprehensive procedures for the production of 89Zr labeled monoclonal antibodies // J Nucl Med. 2003. Vol. 44, no. 8. P. 1271–1281.

[18] Brandt M., Cardinale J., Aulsebrook M. L., et al. An Overview of PET Radiochemistry, Part 2: Radiometals. J. Nucl. Med. 2018;10:1500–1506. https://doi.org/10.2967/jnumed.117.190801.

[19] Brandt M., Cardinale J., Aulsebrook M. L., et al. An Overview of PET Radiochemistry, Part 2: Radiometals // J. Nucl. Med. 2018. Vol. 10. P. 1500–1506. https://doi.org/10.2967/jnumed.117.190801.

[20] Moroz A. A., Chia-Yin L., Wang Y., et al. Preclinical Assessment of 89Zr-atezolizumab Identifies A Requirement For Carrier Added Formulations Not Observed With 89Zr-C4. Bioconjug Chem. 2018;29(10):3476–3482. https://doi.org/10.1021/acs.bioconjchem.8b00632.

[21] Moroz A. A., Chia-Yin L., Wang Y., et al. Preclinical Assessment of 89Zr-atezolizumab Identifies A Requirement For Carrier Added Formulations Not Observed With 89Zr-C4 // Bioconjug Chem. 2018. Vol. 29, no. 10. P. 3476–3482. https://doi.org/10.1021/acs.bioconjchem.8b00632.

[22] Zhukovsky M. V., Zakaly H. M. H. dose coefficients for monoclonal antibodies and antibody fragments labeled by zirconium-89. Rad. Applic. 2018;3(2):152–158. https://doi.org/10.21175 RadJ.2018.03.026.

[23] Zhukovsky M. V., Zakaly H. M. H. dose coefficients for monoclonal antibodies and antibody fragments labeled by zirconium-89 // Rad. Applic. 2018. Vol. 3, no. 2. P. 152–158. https://doi.org/10.21175/RadJ.2018.03.026.

[24] ICRP Publication 128. Radiation Dose to Patients from Radiopharmaceuticals: A Compendium of Current Information Related to Frequently Used Substances. Ann ICRP. 2015;44(2 Suppl):7–321. https://doi.org/10.1177/0146645314558019.

[25] ICRP Publication 128. Radiation Dose to Patients from Radiopharmaceuticals: A Compendium of Current Information Related to Frequently Used Substances // Ann ICRP. 2015. Vol. 44, 2 Suppl. P. 7–321. https://doi.org/10.1177/0146645314558019.

[26] Li М., Dawei J., Todd E., et al. Immuno-PET imaging of VEGFR-2 expression in prostate cancer with 89Zr-labeled ramucirumab. J Cancer Res. 2019;9(9):2037–2046.

[27] Li М., Dawei J., Todd E., et al. Immuno-PET imaging of VEGFR-2 expression in prostate cancer with 89Zr-labeled ramucirumab // J Cancer Res. 2019. Vol. 9, no. 9. P. 2037–2046.

[28] Holland J. P., Caldas-Lopes E., Divilov V., et al. Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab. PLoS ONE. 2010; 5(1): e8859. https://doi.org/10.1371/journal.pone.0008859.

[29] Holland J. P., Caldas-Lopes E., Divilov V., et al. Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab // PLoS ONE. 2010. Vol. 5, no. 1. P. e8859. https://doi.org/10.1371/journal.pone.0008859.

[30] Kristensen L. K., Christensen C., Jensen M. M., et al. Site-specifically labeled 89Zr-DFO-trastuzumab improves immuno-reactivity and tumor uptake for immuno-PET in a subcutaneous HER2-positive xenograft mouse model. Theranostics. 2019; 9(15):4409–4420. https://doi.org/10.7150/thno.32883.

[31] Kristensen L. K., Christensen C., Jensen M. M., et al. Site-specifically labeled 89Zr-DFO-trastuzumab improves immuno-reactivity and tumor uptake for immuno-PET in a subcutaneous HER2-positive xenograft mouse model // Theranostics. 2019. Vol. 9, no. 15. P. 4409–4420. https://doi.org/10.7150/thno.32883.

[32] Bensch F., van der Veen E. L., Lub-de Hooge M. N., et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nature Medicine. 2018;24(12):1852–1858. https://doi.org/10.1038/s41591-018-0255-8.

[33] Bensch F., van der Veen E. L., Lub-de Hooge M. N., et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer // Nature Medicine. 2018. Vol. 24, no. 12. P. 1852–1858. https://doi.org/10.1038/s41591-018-0255-8.

[34] Shanehsazzadeh S., Lahooti A., Shirmardi S. P., et al. Comparison of estimated human effective dose of 67Ga-and 99mTc-labeled bombesin based on distribution data in mice. J Radioanal Nucl Chem. 2015;305:513–520. https://doi.org/10.1007/s10967-015-3995-7.

[35] Shanehsazzadeh S., Lahooti A., Shirmardi S. P., et al. Comparison of estimated human effective dose of 67Ga- and 99mTc-labeled bombesin based on distribution data in mice // J Radioanal Nucl Chem. 2015, Vol. 305. P. 513–520. https://doi.org/10.1007/s10967-015-3995-7.

[36] Shanehsazzadeh S., Lahooti A., Yousefnia H., et al. Comparison of estimated human dose of 68Ga-MAA with 99mTc-MAA based on rat data. Ann Nucl Med. 2015;29(8):745. https://doi.org/10.1007/s12149-015-0997-z.

[37] Shanehsazzadeh S., Lahooti A., Yousefnia H., et al. Comparison of estimated human dose of 68Ga-MAA with 99mTc-MAA based on rat data // Ann Nucl Med. 2015. Vol. 29, no. 8. P. 745. https://doi.org/10.1007/s12149-015-0997-z.

[38] Shanehsazzadeh S., Yousefnia H., Jalilian A. R., et al. Estimated human absorbed dose for 68Ga-ECC based on mice data: comparison with 67Ga-ECC. Ann Nucl Med. 2015;29(6): 475–481. https://doi.org/10.1007/s12149-015-0967-5.

[39] Shanehsazzadeh S., Yousefnia H., Jalilian A. R., et al. Estimated human absorbed dose for 68Ga-ECC based on mice data: comparison with 67Ga-ECC // Ann Nucl Med. 2015. Vol. 29, no. 6. P. 475–481. https://doi.org/10.1007/s12149-015-0967-5.

[40] Standardized uptake value. Wikipedia. 2021. URL: https://en.wikipedia.org/wiki/Standardized_uptake_value.

[41] NCr nude. TACONIC. 2021. URL: https://www.taconic.com/mouse-model/ncr-nude.

[42] ICRP Publication 110. Adult Reference Computational Phantoms. Ann. ICRP. 2009;39(2).

[43] ICRP Publication 110. Adult Reference Computational Phantoms // Ann. ICRP. 2009. Vol. 39, no. 2.

[44] Trial version of Origin/Origin Pro. OriginLab. 2021. URL: https://www.originlab.com/demodownload.aspx.

[45] Erbslöh-Möller B., Dumas A., Roth D., et al. Furosemide-131I-hippuran renography after angiotensin-converting enzyme inhibition for the diagnosis of renovascular hypertension. Am J Med. 1991;90(1):23–29. https://doi.org/10.1016/0002-9343(91)90502-o.

[46] Erbslöh-Möller B., Dumas A., Roth D., et al. Furosemide-131I-hippuran renography after angiotensin-converting enzyme inhibition for the diagnosis of renovascular hypertension // Am J Med. 1991. Vol. 90, no. 1. P. 23–29. https://doi.org/10.1016/0002-9343(91)90502-o.

[47] Andersson M., Johansson L., Eckerman K., et al. IDAC-Dose 2.1, an internal dosimetry program for diagnostic nuclear medicine based on the ICRP adult reference voxel phantoms. EJNMMI Research. 2017;7(1):88. https://doi.org/10.1186/s13550-017-0339-3.

[48] Andersson M., Johansson L., Eckerman K., et al. IDAC-Dose 2.1, an internal dosimetry program for diagnostic nuclear medicine based on the ICRP adult reference voxel phantoms // EJNMMI Research. 2017. Vol. 7, no. 1. P. 88. https://doi.org/10.1186/s13550-017-0339-3.

[49] ICRP Publication 60. Recommendations of the International Commission on Radiological Protection. Ann ICRP. 1991;21(1–3).

[50] ICRP Publication 60. Recommendations of the International Commission on Radiological Protection // Ann ICRP. 1991. Vol. 21, no. 1–3.

[51] ICRP Publication 103. Recommendations of the International Commission on Radiological Protection (Users Edition). Ann ICRP. 2007;37(2–4).

[52] ICRP Publication 103. Recommendations of the International Commission on Radiological Protection (Users Edition) // Ann ICRP. 2007. Vol. 37, no. 2–4.

[53] Laforest R., Lapi S. E., Oyama R., et al. [89Zr] Trastuzumab: Evaluation of Radiation Dosimetry, Safety, and Optimal Imaging Parameters in Women with HER2-Positive Breast Cancer. Mol Imaging Biol. 2016;18(6):952–959. https://doi.org/10.1007/s11307-016-0951-z.

[54] Laforest R., Lapi S. E., Oyama R., et al. [89Zr] Trastuzumab: Evaluation of Radiation Dosimetry, Safety, and Optimal Imaging Parameters in Women with HER2-Positive Breast Cancer // Mol Imaging Biol. 2016. Vol. 18, no. 6. P. 952–959. https://doi.org/10.1007/s11307-016-0951-z.

[55] Meyer J. P., Edwards K. J., Kozlowski P., et al. Selective Imaging of VEGFR-1 and VEGFR-2 Using 89Zr-Labeled Single-Chain VEGF Mutants. J Nucl Med. 2016;57(11): 1811–1816. https://doi.org/10.2967/jnumed.116.173237.

[56] Meyer J. P., Edwards K. J., Kozlowski P., et al. Selective Imaging of VEGFR-1 and VEGFR-2 Using 89Zr-Labeled Single-Chain VEGF Mutants // J Nucl Med. 2016. Vol. 57, no. 11. P. 1811–1816. https://doi.org/10.2967/jnumed.116.173237.

RIGHTS & PERMISSIONS

Chipiga L.A., Petrova A.E., Mosunov A.A., Naurzbaeva L.T., Kushnarenko S.M., Lavreshov D.D., Vodovatov A.V., Stanzhevsky A.A., Maistrenko D.N.